On the TRAIL of a Solution to Trastuzumab Resistance in HER2+ Breast Cancer

A genomic and proteomic analysis of HER2-positive breast cancer cell lines that are resistant to trastuzumab found a deregulation of the cell death pathway known as TRAIL (tumor necrosis factor–related apoptosis-inducing ligand). The finding presents the possibility of targeting this pathway as a way to lessen the impact of trastuzumab resistance in HER2-positive breast cancer.

“Despite the fact that trastuzumab has revolutionized the prognosis of HER2-positive breast tumors, one problem frequently found in the metastatic setting is the appearance of resistance to the drug,” wrote study authors led by Elena Diaz-Rodriguez, of the Spanish National Research Council’s Instituto Investigación Biomédica de Salamanca. “Alternative strategies should be investigated for the therapy of trastuzumab-resistant tumors.”

The researchers conducted a number of analyses on cell lines that are resistant to trastuzumab. The results of the analyses were published in Cancer Letters.

They identified a set of 425 deregulated genes in the resistant cells, when compared with HER2-positive breast cancer cells that were not resistant to trastuzumab. From that, a transcriptomic map was created, which indicated deregulation of cellular functions relating to cell death, DNA damage response, and others.

A further analysis showed that the most deregulated proteins corresponded to TRAIL receptors Death Receptor 4 (DR4) and DR5. A gene set enrichment analysis showed that multiple genes in the TRAIL pathway are deregulated in the resistant cells.

Further experiments showed that this pathway may be targetable, with the potential to overcome resistance. Treatment of normal HER2-positive breast cancer cells with TRAIL slightly reduced their proliferative ability, while treatment of resistant cells had a much more dramatic effect.

The upregulation of the Death Receptor factors plays a role in the sensitivity of the resistant cells to treatment with TRAIL. A subsequent experiment found that downregulation of DR4 decreased that sensitivity, while downregulation of DR5 had a less pronounced effect.

The authors noted that these results confirm a recent study showing a deregulation of the TRAIL pathway in cells resistant to another HER2-targeted agent, lapatinib. The new results, they wrote, “[open] the possibility of acting on this pathway to treat resistance to anti-HER2 therapies and taking advantage of the vulnerability we have described.”

There has been increasing interest in targeting TRAIL in this and other malignancies in recent years. According to Agathe Dubuisson and Olivier Micheau, of INSERM in Dijon, France, in a review in 2017, the first generation of TRAIL or TRAIL receptor agonist antibodies failed to show sufficient efficacy to continue development. However, a second generation of such agents have been developed using a number of strategies designed to increase their bioavailability and efficacy.

“Whereas, it still remains unknown whether DR4- and DR5-targeting therapeutics will meet the requirements to get approval for cancer therapy, a number of these novel formulations raise hope, due to the excellent results obtained from preclinical or early clinical studies,” they wrote. “The next generation of DR4- and DR5-targeting agents are, thus, likely to put hope back on the trail of antitumoral therapeutics.”